R4P Day 3: Mucosal Immunity, Family Strategies, Building the Best HIV Vaccine and More

Welcome to Day 3 of the HIV R4P conference daily round-up! As we've been doing all week, this update offers a selective, whirlwind tour through some of the day's sessions -- all of which are available via webcast 24 hours after they took place. There's lots more information and insight in the conference's liveblog and the Twitter feed #HIVR4P.

Morning Plenaries

This morning's plenary session brought three presentations on mucosal immunology. Mucosa, including the linings of the vagina and the rectum, are the site of sexual transmission. But these locations -- like sex itself -- are simultaneously easy to talk about and difficult to describe with precision. While it's clear HIV acquisition via sex starts at the mucosa, there are still lots of questions about how infection starts -- in what cells -- and how it progresses from the localized site(s) of entry to a disseminated infection in which virus is found in the blood and throughout the body.

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Jake Estes (Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research) provided a vivid look -- complete with 3-D imaging -- at the path of dissemination using a non-human primate model. Estes and his collaborators used viral inoculum that had been carefully selected for non-inflammatory studies. (Interesting fact for the lay person -- the stuff other than the virus that is in a viral challenge can change the mucosa in an animal experiment.) His presentation maps what was found in different animals -- a localized, genital tract infection that may move out into the body via the lymphatic system.

Next, Jo-Ann Passmore (University of Cape Town, National Health Laboratory Service, and CAPRISA) presented on some of the factors in the genital tract that appear to make HIV infection more likely. Sexual transmission via vaginal sex is relatively inefficient -- it doesn't happen every time, or even most times a person is exposed. As Passmore noted, there are conditions, particularly inflammation, that can make a person more susceptible. If one thinks about local HIV exposure as a fire that either goes out -- doesn't result in infection -- or spreads then, Passmore said, "Inflammatory signals are fuels that bring HIV-target cells into the genital tract. If you could block inflammation it would be a very effective way of limiting infection." She identified several inflammatory markers or cytokines in the genital tract of women from the CAPRISA 004 microbicide trialwho acquired HIV. Her talk also touched on the different cytokine profiles found in the blood and concluded with a Venn diagram of inflammation, compartment (blood versus genital tract), inflammation and so on that is worth lingering on for what it suggests about measuring and addressing inflammation as part of HIV prevention. At the end of her talk, Passmore shifted gears from the scientific to the practical and made an important and passionate argument for policy change. "Young women have unacceptably high rates of asymptomatic STIs and bacterial vaginosis" -- conditions linked to inflammation. Given the correlation between inflammation and HIV risk, and the high rates of HIV in young women, she called for "an urgent reevaluation of how appropriate our current STI surveillance and testing guidelines are for sub-Saharan Africa."

Finally, Omu Anzala (Kenya AIDS Vaccine Initiative) gave a thorough and accessible explanation of the importance of mucosal assays as part of HIV prevention trials -- stressing the necessity of gathering information about immune responses in these tissues, as well as the feasibility of doing so in African settings. With a strong focus on Kenyan activity, he described a center of excellence for mucosal work that comprises several collaborating institutions, as well as early work to determine whether nasal sampling could provide relevant information -- a potential way to address the cost and invasiveness of genital biopsies and other sampling. He concluded by raising the priority of looking for broadly neutralizing antibodies at mucosal sites -- and of designing vaccines to induce such defenses.

Other Presentations

We Are Family?: Babies, Mothers, Fathers and the Ongoing Challenges of "PMTCT"

This morning's session [OA.23] on pregnancy intentions, safe conception and prevention of vertical transmission was, if not the first, then at least one of the early examples of a discussion that embraced both PrEP (pre-exposure prophylaxis) for the HIV-negative partner and traditional ART interventions for prevention of vertical transmission. This, in and of itself, is a thrilling development -- since it moves the prevention conversation into a place of shared responsibility and choices for both the HIV-positive and -negative partners in the context of conception. Erika Aaron (Drexler University) [OA23.SY] provided a clear, comprehensive review of "PrEP-ception" decision-making as part of a discussion of the worldwide context of woman-centered PrEP implementation. (Perhaps, as PrEP enters the conversation, we will finally abandon "PMTCT", which foregrounds the mother's role in favor of more neutral terminology.)

PrEP and Option B-plus (ART for life for pregnant and lactating women) are effective strategies, but they only work if they are taken as prescribed. Durban-based researcher Nzwakie Mosery (MatCH) described the role of depression, social support, stigma and structural barriers to care in adherence to ART among 200 HIV-positive women [OA23.02]. Twenty-four percent of women reported depression symptoms; and depression was correlated with adherence challenges, as measured by self report. The information on other barriers spoke volumes about the gaps in effective, accessible HIV and contraceptive services. Sixty percent of the women said that they did not want to be pregnant. One-third of the women attended the clinic on foot, and spent an average of a half an hour to get there -- a barrier under any circumstances, but a tremendous consideration as pregnancy progresses.

These and other presentations in this session complemented the Day 2 (Wednesday) roundtable "Prevention of Mother to Child Transmission Revisited" [RT2], which focused much more intensively on the strategies that could be directed towards the fetus, newborn and infant of an HIV-positive mother to help prevent infection or achieve a functional cure. In remarks from the floor at this session, Susan Allen (Rwanda-Zambia HIV Research Group -- Emory University) presaged her talk at this afternoon's session [RT04.05], which featured an urgent call for integration of couples counseling into prevention trials and services -- nicely summarized by its subtitle, "Most transmissions are in marriage, most pregnancies are not immaculate conceptions, and women aren't just incubators."

Deep Thoughts on Viral Variability

Deep sequencing is a technique that is a strategy for sensitively characterizing rapidly evolving viruses like HIV -- including minor, hard-to-detect variants. Two talks at the morning session on viral transmission [OA.21] highlighted some of the subtle but potentially important distinctions in the virus that establishes infection (founder virus). Even if a person is exposed to several different genetic variants of HIV, infection usually involves a single variant. There is a bottleneck -- still not understood -- created by mucosal defenses that contributes to this phenomenon. Understanding the characteristics of the viruses that establish infection is key for informing vaccines and other strategies that aim to boost immunity in the genital tract. Damien Tully (Ragon Institute) described slight differences in the "genetic footprints" of founder viruses that establish infection in gay men and other men who have sex with men, compared to founder viruses in heterosexual transmission [OA21.05]. Specifically, he identified some site-specific differences in glycosolation -- signature sites -- that might confer some selective advantage on specific viruses that establish infection at the rectal mucosa.

Gustavo Kijak [OA21.06LB] used deep sequencing to look closely at the genetics of founder viruses from people acutely infected with HIV in Thailand and South Africa. He focused his talk on four individuals and described how, although it looked like a single variant established infection, close analysis revealed a small population of a minor variant. This is called "cryptic multiple infection." Soon after infection, the minor variant can very quickly become a larger proportion of the virus found in the blood.

Understanding these fluctuations and the possibility of cryptic multiple infection is key to a working model of what happens during early infection.

Building the Best Possible Vaccine: More on Selecting Adjuvants and Immunogens

This session [OA.25] explored the critical role of adjuvants (immune boosting agents that are formulated as part of a vaccine) and immunogens (the precise elements of HIV selected to present to the immune system). This conference has included many talks related to follow-on work based on RV144, the successful Thai vaccine trial -- and this session added to the conversation. Genoveffa Franchini (National Cancer Institute, USA) presented non-human primate data on a study of an RV144-like regimen formulated with the adjuvant used in the original trial in Thailand (alum) or the adjuvant planned for use in the RV144 follow-on trial (MF59) [OA25.01]. A new adjuvant has been selected in hopes of boosting immunogenicity and, therefore, protection in humans.

Getting Real About Universal Test and Treat

Kwame Shanaube (ZAMBART Project, Zambia) presented preliminary lessons from the ongoing PopART trial that is designed to find out whether a "universal test and treat" (UTT) strategy can be delivered with high uptake and acceptability [OA28.03]. Her opening comments were a great reminder of the reasons why models can't predict, with certainty, what the impact of this or any strategy will be. "They don't take the complexities of real-life scale up" into account, Shanaube said. PopART is still underway so no data was presented, but Shanaube described the tremendous effort needed to recruit and train health workers to deliver home-based testing, and the discovery that in-home testing may not meet everyone's needs. She said a "combination of community models" including work-based VCT and more should be explored -- a relevant finding for ART programs, not just research projects.

Is PrEP Faster Than a Speeding Tampon?

The discussion of what it will take to achieve real-world impact with existing and emerging strategies continued in the afternoon roundtable "Diffusion of Innovation" [RT3]. Presentations presented timelines and experiences for the introduction of various interventions -- from the tampon to female condom to VMMC to PrEP. It can take decades for a product to "catch on", and success is dependent on smart introduction and investment. The panel made clear that product introduction requires the same (and even more) commitment to strategy, resource and planning that product development receive--and questioned why invest in new product development if funders aren't willing to commit to future product delivery.

The Work We Do Together

Eduard Sanders (KEMRI-Wellcome Trust Research Program, Kenya) presented on in-depth work at a coastal Kenyan research site that, over time, addressed community concerns, built trust among gay men and other MSM, as well as site staff skills and comfort in working with this population. Udom Likhitwonnawut (advocate and consultant in Thailand) presented on ongoing, community-led work to ensure implementation of the Good Participatory Practice Guidelines in a country that continues to play a key role in biomedical prevention research [RT4].

This is the last full day of the conference. Tomorrow, everything comes together in a final plenary--and then we return to our work in the real world. Stay tuned for a final update and don't forget to save the date for our post-R4P webinar -- Thursday, November 6 -- on the way forward!

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